癌症基因 z-bo 2020-12-11 696

　　A new study shows that an epigenetic change that has been preserved for more than 400 million years can inactivate some genes related to cancer in the later stages of human development.

　　 Some human cancer genes are also present in zebrafish, but they are "silent" within a few hours after fertilization. This research provides new clues for people to understand how epigenetics has regulated genes in evolutionary history. It also reveals significant differences in the "self-reset" of the epigenome in zebrafish and human embryos, and will guide future epigenetic research. Ozren Bogdanovic, head of the Developmental Epigenomics Laboratory at the Gavin Institute of Medical Research in Sydney, Australia, who led the research, said: “We have shown that humans have preserved embryonic events that can shut down genes related to human cancer. This is interesting, although We don’t know why this happens, but it shows how important it is for human health to keep these genes silent."

　　 Unexpected "relatives"

　　 At first glance, humans and zebrafish (a fish native to South Asia) seem to be unrelated, but in fact, the common evolutionary ancestor of the two can be traced back more than 400 million years.

　　 From a genetic point of view, zebrafish and humans are no different-they share about 87% of their genes. Zebrafish is an important model animal for carrying out life sciences, health sciences, and environmental science research, and is known as "water mice". Chen Feng, a researcher at the South China Botanical Garden of the Chinese Academy of Sciences, pointed out in an interview with the Chinese Journal of Science that zebrafish have the characteristics of strong reproductive capacity, in vitro fertilization and development, transparent embryos, short sexual maturity cycles, and small individuals, making them a functional genome. One of the important model vertebrates in life science research of the age.

　　 Bogdanovic’s team’s research started with DNA “reading”—they set out to study the maintenance of epigenetic changes during embryonic development. These epigenetic changes control the way DNA “reads”.

　　 genes are controlled by methylation to a certain extent, and methylation is a mark on DNA that prevents genes from being read. "Every cell type in the human body, including sperm and eggs, has a unique pattern of DNA methylation marks-chemical tags on DNA can regulate gene activity." Bogdanovic said.

　　Methyl group is formed by the combination of one carbon atom and 3 hydrogen atoms. DNA methylation involves the modification of DNA molecules by methyl groups. As one of the most basic epigenetic phenomena, DNA methylation is the change in gene expression when the DNA sequence of the gene does not change. It is necessary for the normal development process, but it is related to the occurrence and development of tumors. Many important pathophysiological processes within are also closely related.

　　 In the first week after fertilization, humans and other mammals "reset" their DNA methylation patterns, allowing embryos to develop and differentiate into different cell types. Another wave of DNA methylation reset occurred in the embryo's primordial germ cells-the precursors of sperm and egg cells, between the third and seventh weeks of human embryonic development. However, until now, whether the principle of epigenetic reset is evolutionarily conserved in all vertebrates remains a mystery.

　　 The "father image" of zebrafish genes

　　 Researchers first isolated primordial germ cells (precursor cells of sperm and eggs) from zebrafish embryos, and generated whole genome methylation sequencing (WGBS) data—a snapshot of all DNA methylation in the cell. The

　　 research team then discovered the basic differences in DNA methylation between mammalian and zebrafish embryos.

　　 In humans, when an egg is fertilized, most of these DNA methylation tags will be "cleaned" and then gradually methylated again to ensure normal development of the embryo. In contrast, zebrafish embryos retain the father's methyl pattern.

　　 In this study, the Bogdanovic team also found that zebrafish primordial germ cells did not reset their methylation patterns, but inherited the father’s DNA methylation patterns.

　　 This is in sharp contrast to mammals-the DNA methylation signature of mammalian primordial germ cells will be "scanned clean" a second time. The researchers said that this discovery revealed the molecular principles of the development of the reproductive system, and emphasized that zebrafish is a useful experimental model to study how epigenetic characteristics are passed on from generation to generation.

　　 In addition, the researchers also screened how DNA is methylated in the four stages of zebrafish embryo development. They found that 68 genes were methylated and turned off in the early stages of embryonic development, that is, within 24 hours after fertilization. Ksenia Skvortsova, the first author of the paper, said: "Interestingly, most of these genes belong to a group of genes called testicular cancer antigen (CTA). Our research shows that these genes are the earliest in zebrafish and mammals. Genes targeted by'silencing' or DNA methylation."

　　 New insights into ancient mechanisms

　　 The gene encoding CTA is only active in male testes, and is shut down in all other human tissues. For unknown reasons, the CTA gene is reactivated in some cancers, such as melanoma.

　　 "Mammals and fish have very different strategies for embryonic development," Bogdanovic said. "But despite these strategies, their control of CTA genes seems to be conserved throughout evolution."

　　 In addition, DNA methylation markers, as a new minimally invasive detection method, only need to detect a small amount of tissue to obtain sufficient DNA for analysis, and can effectively identify colorectal cancer, lung cancer, breast cancer, liver cancer and other tumors. Researchers from the University of California, San Diego and other institutions have found that using the difference in DNA methylation levels at specific sites, the accuracy of distinguishing normal tissue from tumor tissue in three databases is more than 95%, which is comparable to traditional diagnostic methods, but samples Only a small amount is required, and the process is simpler and faster. In addition, Li Dinggang, technical director of the Oncology Department of Beijing Yanhua Hospital and a member of the Beijing Branch of the Chinese Anti-Cancer Society, told reporters that “cancers generally have a long evolutionary process from gene mutations to out-of-control tumor formation and clinical symptoms.” Therefore, for cancer treatment, Attention should also be paid to early screening.

　　 "But this is only secondary prevention. Primary prevention is causal prevention, including immunization, etc." Li Dinggang said. Etiology prevention refers to preventive measures aimed at pathogenic factors, which are divided into measures aimed at the environment and measures aimed at the body. The disease did not occur at this stage, but certain risk factors already exist, such as pathogen infection, mental overstress, and malnutrition. "These will all increase the risk of disease, and some of the risk factors at this stage can be changed, such as anti-infection, psychological adjustment, strengthening nutrition, etc. This stage can be called the susceptible period."

　　 In any case, zebrafish research provides new clues for understanding human evolution and may have a potential impact on the future of human health. Scientists began to study the potential utility of drugs targeting CTA in the treatment of cancer. "The current research provides more evidence of the importance of CTA and how tightly they are controlled during evolution," Bogdanovic said.